Cell Cycle-Dependent Switch of TopBP1 Functions by Cdk2 and Akt

Liu, Kang; Graves, Joshua D.; Lee, Yu-Ju; Lin, Fang-Tsyr; Lin, Weei-Chin

doi:10.1128/mcb.00599-19

Cited by 11 publications

(10 citation statements)

References 26 publications

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“…TopBP1 also stabilized bloom syndrome helicase (BLM) to maintain genome stability (94). It is often overexpressed in cancer and can bypass control by CDK2 to interact with treslin, leading to enhanced DNA replication (95).…”

Section: Topbp1mentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.

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Section: Topbp1mentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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“…TopBP1 has been suggested to have a role in the control of the DNA replication checkpoint through the collaboration with MDC1 in response to DSBs [9]. More recently, this role has been linked with the interaction of TopBP1 with the kinase CK2 [10,11]. In addition, TopBP1 has been reported to have a role in the regulation of the G2-M checkpoint together with BRCA1 [12] and to mediate the mitotic progression by localising to the mitotic centrosome [13].…”

Section: Introductionmentioning

confidence: 99%

The Role of DNA Topoisomerase Binding Protein 1 (TopBP1) in Genome Stability in Arabidopsis

Parra-Nuñez

Cooper

Sanchez‐Moran

2021

Plants

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DNA topoisomerase II (TOPII) plays a very important role in DNA topology and in different biological processes such as DNA replication, transcription, repair, and chromosome condensation in higher eukaryotes. TOPII has been found to interact directly with a protein called topoisomerase II binding protein 1 (TopBP1) which also seems to have important roles in DNA replication and repair. In this study, we conducted different experiments to assess the roles of TopBP1 in DNA repair, mitosis, and meiosis, exploring the relationship between TOPII activity and TopBP1. We found that topbp1 mutant seedlings of Arabidopsis thaliana were hypersensitive to cisplatin treatment and the inhibition of TOPII with etoposide produced similar hypersensitivity levels. Furthermore, we recognised that there were no significant differences between the WT and topbp1 seedlings treated with cisplatin and etoposide together, suggesting that the hypersensitivity to cisplatin in the topbp1 mutant could be related to the functional interaction between TOPII and TopBP1. Somatic and meiotic anaphase bridges appeared in the topbp1 mutant at similar frequencies to those when TOPII was inhibited with merbarone, etoposide, or ICFR-187. The effects on meiosis of TOPII inhibition were produced at S phase/G2 stage, suggesting that catenanes could be produced at the onset of meiosis. Thus, if the processing of the catenanes is impaired, some anaphase bridges can be formed. Also, the appearance of anaphase bridges at first and second division is discussed.

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“…Oligomerization of TopBP1 inhibits its binding to ATR and therefore inhibits ATR activation ( 10 ). Oligomerization of TopBP1 also inhibits its binding to Treslin and prevents reinitiation of DNA replication in S/G2 phases ( 11 ). However, at the same time, oligomerization of TopBP1 induces its binding to E2F1 and MIZ1, thereby inhibiting E2F1-dependent apoptosis as well as MIZ1-dependent p21 Cip1 expression ( 9 ).…”

mentioning

confidence: 99%

Overexpression of TopBP1, a canonical ATR/Chk1 activator, paradoxically hinders ATR/Chk1 activation in cancer

Liu

Graves

Lin

et al. 2021

Journal of Biological Chemistry

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Topoisomerase IIβ-binding protein 1 (TopBP1) is involved in cellular replication among other functions and is known to activate ATR/Chk1 during replicative stress. TopBP1 is also expressed at high levels in many cancers. However, the impact of TopBP1 overexpression on ATR/Chk1 activation and cancer development has not been investigated. Here we demonstrate that the degree of ATR/Chk1 activation is regulated by TopBP1 in a biphasic, concentration-dependent manner in a nontransformed MCF10A cell line and several cancer cell lines, including H1299, MDA-MB468, and U2OS. At low levels, TopBP1 activates ATR/Chk1, but once TopBP1 protein accumulates above an optimal level, it paradoxically leads to lower activation of ATR/Chk1. This is due to the perturbation of ATR–TopBP1 interaction and ATR chromatin loading by excessive TopBP1. Overexpression of TopBP1 thus hinders the ATR/Chk1 checkpoint response, leading to the impairment of genome integrity as demonstrated by the cytokinesis-block micronucleus assay. In contrast, moderate depletion of TopBP1 by shRNA in TopBP1-overexpressing cancer cells enhanced ATR/Chk1 activation and S-phase checkpoint response after replicative stress. The clinical significance of these findings is supported by an association between TopBP1 overexpression and genome instability in many types of human cancer. Taken together, our study illustrates an unexpected relationship between the levels of TopBP1 and the final functional outcome and suggests TopBP1 overexpression as a new mechanism directly contributing to genomic instability during tumorigenesis.

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Cell Cycle-Dependent Switch of TopBP1 Functions by Cdk2 and Akt

Cited by 11 publications

References 26 publications

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

The Role of DNA Topoisomerase Binding Protein 1 (TopBP1) in Genome Stability in Arabidopsis

Overexpression of TopBP1, a canonical ATR/Chk1 activator, paradoxically hinders ATR/Chk1 activation in cancer

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